Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

High molecular weight kininogen (HK) is a plasma protein that is cleaved by plasma kallikrein in the clinical settings of sepsis and chronic inflammatory diseases such as rheumatoid arthritis and Crohn's disease. This proteolytic event results in a nonapeptide, bradykinin (BK), and a kinin-free derivative of HK, namely HKa. BK promotes angiogenesis by upregulation of bFGF through the B1 receptor or by stimulation of VEGF formation via the B2 receptor. Kininogen-deficient rats show diminished angiogenesis when neovascularization is stimulated. The formation of HKa results in exposure of domain 5 (D5). HKa or D5 inhibit endothelial cell migration and proliferation, both of which are needed for angiogenesis. In the chicken chorioallantoic membrane assay when neovascularization is stimulated by bFGF or VEGF, HKa or D5 inhibit angiogenesis. Monoclonal antibody C11C1, which prevents binding of HK to endothelial cells, also limits its conversion to BK thus downregulating angiogenesis. In vivo, mAb C11C1 inhibits tumor angiogenesis in mice as well as in experimental inflammatory arthritis and inflammatory bowel disease in Lewis rats. In vitro HKa or D5 inhibits endothelial cell adhesion to vitronectin and fibrinogen, resulting in anokis and apoptosis. The HKa receptor, uPAR, forms a signaling complex containing the integrin alphavbeta3 or alpha5beta1, caveolin, Src kinase Yes, focal adhesion kinase and paxcillin. HKa physically disrupts the complex by interfering with the binding of vitronectin to uPAR. Both mAb C11C1 and D5 have potential applications for controlling unwanted angiogenesis in inflammation and cancer.
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PMID:Regulation of angiogenesis by the kallikrein-kinin system. 1684 60

Conventional systemic treatments for patients with psoriasis are associated with multiple adverse effects that require continuous monitoring. The introduction of new biological agents such as etanercept, a fully human fusion protein, has permitted individualisation of patients' treatment according to disease stage. The drug is a competitive inhibitor of tumour necrosis factor-alpha (TNFalpha) that prevents interaction between this cytokine and its cell surface receptors. Etanercept also modulates the activity of other inflammatory cytokines and does not induce complement-mediated cell lysis in vitro. The main source of information regarding etanercept safety comes from studies in patients with rheumatoid arthritis. The most common adverse effect during drug administration is mild injection site reactions. There is no increase in the overall incidence of infections compared with placebo, although there have been several reports of infections caused by intracellular organisms (Mycobacterium tuberculosis, Listeria monocytogenes, and Mycobacterium avium intracellulare). Therefore, combination of this drug with corticosteroids must be carefully monitored and should be avoided in patients with established sepsis. There are no data showing that treatment with etanercept results in an increase in the occurrence of malignant neoplasms. However, caution is recommended in use of etanercept in patients with a current or past history of demyelinating disease. Etanercept must be used with extreme caution in patients with heart failure because of several reports indicating a worsening or de novo occurrence of congestive heart failure while receiving the drug. Monitoring of autoantibodies is not currently considered necessary as they do not predict response, toxicity or autoimmune events. The presence of non-neutralising antibodies to the TNF receptor fragment or other protein components of etanercept has not been related to a decrease in drug response or adverse reactions. Etanercept does not generally modify the course of inflammatory bowel disease. When combined with other systemic therapies for psoriasis, current data do not show an increase in adverse events. In patients with hepatitis C viral infection, etanercept does not increase transaminase levels or viral load and in some instances has allowed the concomitant use of interferon which had previously been discontinued because of a worsening of psoriasis. Etanercept is rated as a US FDA category B drug in pregnancy. However, its use is not recommended in pregnant women unless the benefit-risk ratio greatly favours its use. Etanercept is not recommended for use in lactating women. Etanercept represents a relevant treatment for psoriasis, efficacious over many weeks and safe but special care should be taken to avoid the potential risks.
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PMID:Safety of etanercept in psoriasis: a critical review. 1687 41

Azathioprine, an analog of 6-mercaptopurine has been used as a steroid-sparing agent in the treatment of inflammatory bowel disease for over 30 years. Hypersensitivity reactions to azathioprine including fever, myalgia, arthralgia, rash are well documented in the literature. Here, we report 2 cases of azathioprine hypersensitivity in patients with inflammatory bowel disease manifesting with the unusual symptom of profound muscular weakness resulting in inability to perform simple tasks such as lifting even light objects, sitting upright, and walking a few steps. Development of severe weakness raised concern about myositis, rhabdomyolysis, myopathy, and sepsis in these patients. Discontinuation of azathioprine resulted in prompt improvement of muscular weakness, and rechallenge led to recurrence of similar symptoms within hours. These observations suggest that the development of muscular weakness in patients on azathioprine should be considered as an adverse effect of the drug. Failure to recognize this adverse outcome can lead to prolonged periods of muscular weakness in this group of patients.
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PMID:Severe muscular weakness: an unusual adverse effect of azathioprine therapy. 1691 6

Colorectal cancer is the most common malignant complication in patients who have IBD. The disease is difficult to diagnose because there is an overlap in symptoms in patients who have colon cancer and those who have IBD. Much has been learned about the incidence of colorectal cancer in patients who have IBD and its correlation with disease activity, duration, and anatomic location; however, almost no data are available regarding specific therapeutic considerations during adjuvant or palliative chemotherapy for these patients with respect to their underlying disease. Patients who have IBD who develop colorectal cancer are at higher risk for developing severe diarrhea during chemotherapy that may be due to the toxic effects of cytotoxic drugs or a flare of the IBD. Continuous infusional 5-FU alone, in combination with leucovorin, or in combination with oxaliplatin (FOLFOX) seems to be tolerated best. Bolus infusions of 5-FU (Roswell Park or Mayo regimens) and combination therapy of irinotecan with 5-FU should be avoided because of severe diarrhea and the possibility of sepsis. When diarrhea develops or worsens, empiric aminosalicylates may be given. Although it is theoretically possible that anti-EGFR therapies could affect IBD activity adversely, clinical experience with cetuximab in patients who have colorectal cancer has not shown any significant gastrointestinal side effects. Therefore, it seems reasonable to use it in patients who have colorectal cancer and IBD. The administration of bevacizumab has been associated with rare episodes of intestinal perforation; it should be used with great care in patients who have IBD. More studies and an integrative, multidisciplinary approach from oncologists and gastroenterologists are needed to provide optimal care for patients who have IBD during chemotherapy for colorectal cancer
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PMID:Systemic treatment of patients who have colorectal cancer and inflammatory bowel disease. 1695 47

The induction of immune tolerance is critical for the prevention of autoimmunity and the maintenance of immune homeostasis. The identification of factors involved in the maintenance or restoration of such tolerance has become the focus of new therapies for inflammatory and autoimmune diseases. Cortistatin, a recently discovered cyclic neuropeptide related to somatostatin, has emerged as a potential endogenous antiinflammatory factor based on its production by, as well as its binding to, immune cells. Thus, cortistatin has been found to downregulate the inflammatory response mediated by activated macrophages. The present work reviews various recent studies involving different experimental models of sepsis, rheumatoid arthritis and inflammatory bowel disease, demonstrating that cortistatin treatment offers great benefits at both the clinical and pathological levels. These include the downregulation of both inflammatory and Th1-mediated autoimmune disease components and the emergence of regulatory T cells (Treg) that suppress autoreactive T cells, both of which contribute to the restoration of immune tolerance. While many questions need to be resolved, cortistatin appears to be an exciting and promising candidate for the treatment of several chronic inflammatory diseases and autoimmune disorders.
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PMID:Cortistatin as a potential multistep therapeutic agent for inflammatory disorders. 1708 Feb 2

In 1978, Price introduced the concept of indeterminate colitis to describe cases in which colonic resections had been undertaken for chronic inflammatory bowel disease (CIBD), but a definitive diagnosis of either of the classical types of CIBD, ulcerative colitis and Crohn's disease, was not possible. This was especially apposite in cases of acute fulminant disease of the colorectum. More recently, the term indeterminate colitis has been applied to biopsy material, when it has not been possible to differentiate between ulcerative colitis and Crohn's disease. In our opinion, and in those of other workers in this field, the term should be restricted to that originally suggested by Price. This then provides a relatively well-defined group of patients in whom the implications and management of the disease are becoming much clearer. Cases where there are only biopsies with CIBD, but equivocal features for ulcerative colitis and Crohn's disease, should be termed 'CIBD, unclassified', 'equivocal/non-specific CIBD' or IBD unclassified (IBDU), in line with recent recommendations. When the diagnosis is correctly restricted to colectomy specimens, there is now good evidence that the majority of cases will behave like ulcerative colitis. Furthermore, the diagnosis should not be a contraindication to subsequent pouch surgery. When the latter is undertaken, surgeons and patients can expect an increased complication rate, compared with classical ulcerative colitis, especially of pelvic sepsis, but most patients fare well. Only very occasional patients, around 10%, will eventually be shown to have Crohn's disease. This review describes the pathology of cases appropriately classified as indeterminate colitis and the implications of that diagnosis. It also highlights recent advances in its pathological features, clinical management and its immunological and genetic associations.
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PMID:Indeterminate colitis: definition, diagnosis, implications and a plea for nosological sanity. 1720 23

The entero-cutaneous fistulas (ECF) are abnormal communications between intestine and abdominal skin. They can occur spontaneously, or after an injury or a surgical procedure. They are associated with a high rate of morbidity and mortality. Spontaneous fistulas can mainly occur in patients affected by cancer, inflammatory bowel disease, diverticulitis, appendicitis, as a result of radiotherapy or injuries. Surgical procedures, carried out in case of neoplastic diseases, inflammatory bowel disease, adhesions removal, represent the primary cause in the development of a postoperative fistulas. Malnourishment, poor general conditions of the patient, high output fistula along with anatomical site of development, and the presence of abscesses, represent the negative factors influencing the spontaneous healing of fistulas. The experience reported here is about three ECF cases occurred after surgery and treated only with medical therapy. The first case is a woman in good general conditions who underwent surgery to remove a recurrent retroperitoneal myxoid liposarcoma situated in the right lower quadrant. The patient had never undergone surgery for an intestinal resection. The other two patients analyzed were affected by sepsis and metabolic unbalance and had developed a fistula after colonic resection. Fluids and electrolytes adjustments and sepsis management have preceded any other kind of therapy. Continuous infusion with somatostatin, fast, proton pump inhibitors and loperamide have been taken up to decrease secretions and intestinal motility. Total parenteral nutrition has been essential to recover nutritional status and improve patients' general conditions. In order to heal and protect peri-fistula skin we have used sterile washing solutions, absorbable ionic exchange resin, silver and polyurethanes based medications and colostomy bags adhesive systems. Since surgical treatment of ECF is associated with high rates of morbidity and mortality, conservative treatment should always be taken into consideration. When conservative treatment fails, delayed surgical intervention has been related to a higher rate of success. The purpose of this study is to describe diagnostic and therapeutic guidelines to general surgeons, like ourselves, whenever they have to deal with ECF cases.
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PMID:[Diagnostic and therapeutic guidelines for entero-cutaneous fistulas. Personal experience and literature review]. 1764 89

It has now been over 10 years since Jan-Ake Gustafsson revealed the existence of a second form of the estrogen receptor (ERbeta) at a 1996 Keystone Symposium. Since then, substantial success has been made in distinguishing its potential biological functions from the previously known form (now called ERalpha) and how it might be exploited as a drug target. Subtype selective agonists have been particularly useful in this regard and suggest that ERbeta agonists may be useful for a variety of clinical applications without triggering classic estrogenic side effects such as uterine stimulation. These applications include inflammatory bowel disease, rheumatoid arthritis, endometriosis, and sepsis. This manuscript will summarize illustrative data for three ERbeta selective agonists, ERB-041, WAY-202196, and WAY-200070.
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PMID:Preclinical characterization of selective estrogen receptor beta agonists: new insights into their therapeutic potential. 1782 76

The short bowel syndrome (SBS) can result from a variety of conditions, including postoperative complications and malignancy. Continence-preserving operations are generally performed for either ulcerative colitis (UC) or familial polyposis (FAP). These procedures can be associated with high morbidity and the potential for future malignancy. Our aim was to determine the causes and consequences of SBS in patients undergoing these procedures. Twenty-four patients (12 men and 12 women) 18 to 64 years of age were identified with SBS after continence-preserving procedures. Eighteen had pelvic procedures, and six had continent ileostomies. All SBS patients had a proximal ostomy. Remnant length measured <60 cm in five patients, 60-120 cm in ten patients, and >120 cm in nine patients. Overall 13 patients required long-term PN. Four FAP patients with desmoid tumors died. One patient with UC underwent intestinal transplant and expired. Follow-up ranges from 6 to 192 months. Overall 14 patients had UC, nine had FAP, and one had functional disease. Eight patients with an initial diagnosis of UC had subsequent Crohn's disease necessitating further resection and pouch excision. Eight patients (five with UC, two FAP, and one with functional disease) had postoperative complications, including obstruction or mesenteric ischemia requiring resections. One UC patient developed adenocarcinoma in a continent ileostomy. Seven of the nine FAP patients required resection for desmoid tumors. Six of these underwent resection alone. Three died at 10, 11, and 13 months after SBS from liver failure and sepsis while awaiting transplant. One patient has recurrent desmoid at 30 months, another is alive and well at 48 months, and the other patient, who was not a transplant candidate, died from an unrelated cardiac operation at 23 months. A single patient underwent resection with simultaneous multivisceral transplantation. SBS can develop after continence-preserving procedures. This occurs with inflammatory bowel disease when unsuspected Crohn's disease is present or complications occur. SBS related to desmoid tumors has a poor prognosis in patients undergoing resection alone. A more aggressive approach to intestinal transplantation in these patients may be warranted.
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PMID:Short bowel syndrome after continence-preserving procedures. 1796 30

Interleukin-11 (IL-11) is a cytokine which interacts with a variety of haemopoietic and non-haemopoietic cell types. Recombinant human IL-11 (rhIL-11; oprelvekin) is produced in Escherichia coli and differs from the naturally occurring protein only in the absence of the amino-terminal proline residue. In synergy with other factors, rhIL-11 stimulates the growth of myeloid, erythroid, and megakaryocyte progenitor cells in vitro. In vivo, rhIL-11 is active in mice, rats, dogs, guinea pigs, hamsters and non-human primates, where the principal activity measured was stimulation of megakaryocytopoiesis and thrombopoiesis. rhIL-11 has shown benefit in 2 clinical trials by significantly reducing severe chemotherapy-induced thrombocytopenia. In addition to its thrombopoietic activity, rhIL-11 has also shown activity in models of acute gastrointestinal mucosal damage. rhIL-11 enhanced survival in mice following cytoablative therapy and in a hamster model of chemotherapy-induced oral mucositis, where treatment with rhIL-11 was associated with decreased mucosal damage, accelerated healing and reduced numbers of deaths. rhIL-11 is currently in clinical trials for the treatment of chemotherapy-induced mucositis. In rat models of acute colonic injury and inflammatory bowel disease, rhIL-11 treatment reduced intestinal mucosal damage and alleviated clinical signs. rhIL-11 has direct effects on activated macrophages to reduce the production of pro-inflammatory mediators. In animal models of endotoxaemia, rhIL-11 treatment reduced serum levels of pro-inflammatory cytokines and blocked hypotension. rhIL-11 increased survival in models of Gram-negative sepsis and toxic shock. Based on these studies, rhIL-11 is currently in clinical trials for treatment of Crohn's disease. Other inflammatory conditions are being further evaluated. Mechanistically, rhIL-11 functions at many levels to control inflammation, ameliorate tissue damage and maintain haemostasis in the face of trauma or infection. rhIL-11 has direct effects on hepatocytes, inducing the production of acute phase reactant proteins, haem oxygenase and tissue inhibitor of metalloproteinase-1 (TIMP-1). TIMP-1 expression can also be induced in synoviocytes and chondrocytes by treatment with rhIL-11. rhIL-11 administration has been associated with increased plasma levels of von Willebrand factor and fibrinogen. rhIL-11 treatment potentially offers multiple benefits for cancer chemotherapy patients, such as prevention of thrombocytopenia, gastrointestinal epithelial protection and subsequent reduction of mucositis, and amelioration of inflammatory complications. In addition, rhIL-11 is being evaluated further in the treatment of inflammatory disorders such as inflammatory bowel disease, rheumatoid arthritis and sepsis.
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PMID:Interleukin-11. 1803 Nov 4


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